WO2023152658A1 - Slow release drospirenone tablet composition - Google Patents

Slow release drospirenone tablet composition Download PDF

Info

Publication number
WO2023152658A1
WO2023152658A1 PCT/IB2023/051128 IB2023051128W WO2023152658A1 WO 2023152658 A1 WO2023152658 A1 WO 2023152658A1 IB 2023051128 W IB2023051128 W IB 2023051128W WO 2023152658 A1 WO2023152658 A1 WO 2023152658A1
Authority
WO
WIPO (PCT)
Prior art keywords
drospirenone
pharmaceutical composition
contraceptive
active
polymers
Prior art date
Application number
PCT/IB2023/051128
Other languages
French (fr)
Inventor
Vijaya Kumar Thommandru
Subhasis Das
Romesh Jha
Original Assignee
Lupin Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lupin Limited filed Critical Lupin Limited
Publication of WO2023152658A1 publication Critical patent/WO2023152658A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention relates to compositions of drospirenone.
  • the drospirenone compositions of the present invention exhibit a slow dissolution profile. Further, the compositions are essentially free of any estogenic components and are therefore progestogen-only contraceptives.
  • COCs Combined Oral Contraceptives
  • POCs Progestogen-Only Contraceptives
  • COCs have displayed a superior overall contraceptive efficacy and safety record.
  • the progestin component of COCs contributes to the principle contraceptive mechanisms of action, whereas the estrogen component functions for cycle control as well as the ovulation inhibitory action of progestin.
  • application of COCs is found to develop undesirable health risks like frequent cardiovascular events, other intolerable adverse effects and is not suggested for non-breastfeeding women in the immediate postpartum period or in breastfeeding women during the initial 6 months of breastfeeding.
  • Estrogen-free, Progestogen-Only Contraceptives are a valuable option in women who prefer to take an oral hormonal contraceptive, and are ineligible for, or choose not to use, COCs. Even though POCs may exhibit considerable disadvantages like low contraceptive reliability, daily intake of POCs at the same time without a pill-free or placebo interval, remarkably altered bleeding patterns for women who take POCs leading to amenorrhea or unscheduled bleeding or spotting, but unlike the combined contraceptive pills, POCs possess the benefit of circumventing the administration of estrogens and hence a decreased risk of venous thromboembolism (VTE) and fewer metabolic changes in women seeking oral contraception and are contraindicated for estrogens (due to migraine or cardiovascular risk factors such as hypertension, hyperlipidemias, obesity, diabetes, smoking habits, etc.).
  • VTE venous thromboembolism
  • Drospirenone (6b, 7b : 15b, 16b-Dimethylen-3 -oxo- 17 a-pregn-4-ene-21,17- carbolactone; CAS: 67392-87-4) is a synthetic progestogen which closely resemble the pharmacological activity of natural progesterone. Drospirenone can be prepared by widespread methods defined in the prior art, for instance, in U.S. 4,129,564, WO9806738, EPl 1746101 or W02006061309. The method described in W02006061309 may be particularly suitable for preparing drospirenone.
  • Drospirenone (“DRSP”) lacks androgenic, glucocorticoid and antiglucocorticoid activity, but exerts robust anti-mineralocorticoid activity by blocking aldosterone receptors, which increases sodium and water excretion. Drospirenone also possess antiandrogenic activity which helps to resist the effects of naturally occurring androgens by hindering the binding of dihydrotestosterone (DHT) to its receptor and inhibiting androgen synthesis in the ovaries helping to treat acne and hirsutism. Also, oral daily doses of at least 3 mg of drospirenone in combination with an estrogen, has been found to effectively inhibit ovulation over a single treatment cycle of 21 days.
  • DHT dihydrotestosterone
  • Drospirenone as a contraceptive ingredient is commercially available mostly as combined oral pills under the name of Yasmin R TM (3mg DRSP; 0.03mg EE), Yaz R TM (3 mg DRSP; 0.02mg EE), Angeliq R TM (0.5 mg DRSP; Img EE) and Yasminelle R TM (3 mg DRSP; 0.02mg EE) comprising ethinylestradiol (EE) and drospirenone in micronized form, which elevates it’s in vitro dissolution rate leading to rapid absorption and ensures enhanced oral bioavailability.
  • Yasmin R TM 3mg DRSP; 0.03mg EE
  • Yaz R TM (3 mg DRSP; 0.02mg EE)
  • Angeliq R TM 0.5 mg DRSP; Img EE
  • Yasminelle R TM (3 mg DRSP; 0.02mg EE) comprising ethinylestradiol (EE)
  • WO2009138224 relates to pharmaceutical compositions comprised of micronized drospirenone in alone or in combination with an estrogen and other excipients, which exhibit a rapid in vitro dissolution of drospirenone.
  • WO2009138224 teaches that, co-milling of drospirenone with an appropriate carrier is an effective method to produce amorphous drospirenone in a co-milled state with pharmaceutically acceptable carrier, which possess rapid in vitro dissolution and accordingly enhanced oral bioavailability.
  • European patent EP1214076B 1 reveals that the micronized form of drospirenone possess considerably enhanced in-vitro dissolution rate, which appears to be a necessary condition for obtaining a good bioavailability via the oral route.
  • the rapid in vitro dissolution rate of drospirenone also result in an improved in vivo absorption of drospirenone which helps drospirenone to surpass its degradation by gastric or intestine environments.
  • rapid in vitro dissolution of drospirenone means that, when the composition comprising active contraceptive drug, is subjected to an in vitro dissolution method such as USP apparatus II (Paddle) Method II, at least 70% of the drospirenone is dissolved within 30 minutes.
  • W02012000981 teaches a pharmaceutical composition comprising drospirenone in non-micronized and essentially crystallized form, as the sole active pharmaceutical agent, with slow dissolution rate of drospirenone in vitro and which exhibit a significantly reduced mean Cmax value associated with a delayed mean t m ax value for drospirenone.
  • WO2009138224 further teaches drospirenone possess a low chemical stability and thus gets rapidly degraded into pharmacologically inactive entity under acidic condition. Chemical and physiological properties of drospirenone gets altered as it undergoes hydrolysis under alkaline conditions.
  • micronization of a very potent active pharmaceutical agent such as drospirenone, possess several disadvantages like: contamination due to residues of the milling media produced from erosion of surfaces, leading to chemical destabilization of the newly-formed particles; structural changes or amorphous regions or crystal defects created during milling of drug forms may result in thermodynamically unstable particles, leading to amorphous-crystalline interconversions of the drug during storage, alteration of particle size distribution, specific surface area, chemical and physical reactivity, dissolution or overall performance of the drug product; caking and chemical degradation may occur at high grinding temperatures in case of temperature sensitive materials; hazards from dust may become acute during milling or grinding and can be dangerous for health of workers as a result of inhalation of dust generates during milling of a potent drug.
  • the present invention discloses a pharmaceutical compositions wherein the pharmaceutical compositions hereby comprises of active contraceptive ingredients which are specifically Progestogen-Only Contraceptives ("POCs”) for inhibiting ovulation.
  • active contraceptive ingredients which are specifically Progestogen-Only Contraceptives ("POCs") for inhibiting ovulation.
  • POCs Progestogen-Only Contraceptives
  • the pharmaceutical composition comprising an active contraceptive moiety is found to be effective when administered for a 28-day daily dosing regimen.
  • a patient is allowed to skip up to 4 doses within 28-day daily dosing regimen period, after the inceptive doses of the contraceptive drug has successfully established its contraceptive effect in the patient.
  • the 4 doses can be skipped on non-consecutive days.
  • the 4 doses can be skipped on consecutive days.
  • patient can skip up to two doses of the active contraceptive drug on non- consecutive days, but the skipped dose of the active contraceptive drug is procured within about 24 hours after the two non-consecutive days of skipped doses.
  • the active contraceptive drug may still be able to retain its property of inhibiting ovulation.
  • contraceptive effect in a patient may be established by the active contraceptive drug after administration of at least a first, at least a second or at least a third 28-day daily dosing regimen to the patient.
  • the patient may need to be administered with 21 to 28 active dosage units comprising an active contraceptive drug in a pharmaceutical composition.
  • the 28- day daily dosing regimen may further comprise administration of 1 to 7 placebos, in the span of the 28-day daily dosing regimen when the active dosage units are not allotted to the patient.
  • the POCs may be selected from one or more of the group comprising of drospirenone, 17-hydroxy progesterone esters, 19-nor-17-hydroxy progesterone esters, 17.alpha.-ethinyltestosterone and derivatives thereof, 17.alpha.-ethinyl-19-nor-testosterone and derivatives thereof, norethindrone, norethindrone acetate, norgestrienone, norelgestromin, norgestrel, ethynodiol diacetate, dydrogesterone, medroxy-progesterone acetate, norethynodrel, etonorgestrel, norgestimate, allylestrenol, medrogestone, gestodene, lynoestrenol, ethisterone, fuingestanol acetate, dimethiderome, cyproterone acetate, le
  • the active ingredient in the POC may be drospirenone, wherein drospirenone is the only active ingredient present in the pharmaceutical composition of the present invention.
  • each daily dose of drospirenone may comprise a dosage amount of at least about 2 mg.
  • each single dosage of the pharmaceutical composition of the present invention comprises essentially of 2 mg to 6 mg of Drospirenone.
  • each daily dose of drospirenone can be between 3mg to 4.5mg. In a preferred embodiment the daily dose of drospirenone is 4mg.
  • the composition comprises of the active contraceptive drug in non-micronized amorphous form.
  • amorphous form of the active contraceptive drug can be achieved by solubilizing the active contraceptive drug in the organic solvent with the addition of hydrophobic polymers and copolymers, followed by spray drying in fluidized bed processor.
  • the amorphous drospirenone refers to ideally about 100 wt% drospirenone of the total weight of drospirenone is present in amorphous form.
  • the amorphous dospirenone in the present invention can be designated as a solid that does not confer a crystalline order and thus, is devoid of distinct peaks in a Powder X-ray diffraction (P-XRD) pattern.
  • P-XRD Powder X-ray diffraction
  • preferably no crystalline drospirenone is detected through measurement of powder X-ray diffraction (P-XRD).
  • the pharmaceutical composition of the present invention may additionally comprise desirable pharmaceutically acceptable excipients and adjuvants, selected from the group comprising of diluents, lubricants, hydrophobic polymers, plasticizers.
  • Hydrophobic polymers used in the pharmaceutical composition of the present invention is selected from group comprising of pharmaceutically acceptable hydrophobic polymers selected from acrylic polymers including without limitation copolymers of methyl acrylate, methyl methacrylate and methacrylic acid, epoxy polymers, polyethylene polymers, polystyrene polymers, polyvinylchloride (PVC) polymer, polytetrafluorethylene polymer, polydimethylsiloxane polymer, polyesters, and polyurethanes, or combination thereof.
  • the polymer is an acrylic polymer Plasticizers can be used in combination with the hydrophobic polymers.
  • Suitable plasticizers can be selected from the group comprising of dibutyl sebacate, triacetin, triethyl-citrate, acetyl tributyl citrate, acetyl triethyl citrate polyethylene glycol, polyethylene glycol monomethyl ether, glycerin, sorbitol sorbitan solutions, castor oil, diacetylated monoglycerides.
  • Diluents are selected from a group comprising celluloses and cellulose derivatives, such as microcrystalline cellulose, powder cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, or combination thereof.
  • the pharmaceutical composition of the present invention may further comprise one or more lubricants selected from stearic acid and derivatives thereof, such as calcium stearate, sodium stearyl fumarate or magnesium stearate, glycerol stearate and hydrogenated vegetable oil or combination thereof.
  • stearic acid and derivatives thereof such as calcium stearate, sodium stearyl fumarate or magnesium stearate, glycerol stearate and hydrogenated vegetable oil or combination thereof.
  • the patient is a female patient and may endure several conditions such as, a higher risk for developing venous thromboembolism on administration of estrogen administration of estrogen, acquired or genetic thrombophilia or hypercoagulability, an age of 35 years and above, and above, smoking habits like cigarettes smoking, more vulnerable towards stroke, sickle-cell anemia, increased threat of myocardial infarction, and lactating women.
  • the female patient is deemed to be overweight and obese and thus possess a BMI of about 25.0 kg/m 2 or more.
  • a patient is considered to be overweight if BMI of the patient is about 25.0 kg/m 2 to about 29.9 kg/m 2 or if the BMI of the patient is about 30 kg/m 2 or more.
  • the female patient may possess several other disorders like liver disease, renal disorders, adrenal related disorders, enhanced vulnerability towards hyperkalemia, chronic conditions treated with medicines like non-steroidal anti-inflammatory drugs, potassium-sparing diuretics, potassium supplementation medication, Angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor antagonists and heparin, that may elevate the risk of hyperkalemia.
  • ACE Angiotensin-converting enzyme
  • evaluation of the pharmaceutical compositions comprising active contraceptive drugs in a non-micronized amorphous form, by dissolution tests is disclosed, wherein the daily active oral dosage unit comprising at least about 2mg of the contraceptive moiety is subjected to an in vitro dissolution test according to the USP apparatus II (Paddle) Method .
  • the dissolution profile is found to be such that (i) not more than 50% of the active drug initially available in the daily active dosage unit is dissolved within 30 minutes, and (ii) at least 50% of the active drug is found to be dissolved within a time range from about 3 hours to about 4 hours.
  • the methods of treatment and administering an active contraceptive drug may include building a pharmacokinetic profile that comprises of mean Tmax ranging from about 2.2 hrs to about 6 hrs, and a mean Cmax less than about 30 ng/ml, of the contraceptive drug in the patient body.
  • the pharmacokinetic profile is evaluated in said patient after orally administering a single daily dosage unit of the active contraceptive drug to the patient in fasting condition.
  • the pharmacokinetic profile further comprises an AUCoh-tiast, not less than about 300 ng*h/ml.
  • the AUCoh-tiast is not less than about 350 ng*h/ml.
  • the pharmaceutical composition may be formulated as a single daily active dosage unit for administration to a patient having a BMI of about 25 kg/m 2 or more for at least a portion of a treatment cycle.
  • the pharmaceutical composition after the administration of the pharmaceutical composition for initial treatment cycle, reduces the number of days of bleeding events in the patient that exceeds an average of about 20%, about 15%, about 10%, about 8%, or about 5% per treatment cycle in consecutive treatment cycles of administration.
  • kits also relate to kits that comprises of several packaging units. These packaging unit comprises dosage units with an active drug that provides certain pharmacokinetic parameters.
  • the packaging units in the kits comprises 21 to 28 daily active dosage units comprising an active drug and wherein a single active dosage unit.
  • Fig 1 Overlay PXRDs of Drospirenone active pharmaceutical ingredient used; Drospirenone composition after manufacture and post 3 months storage; Placebo composition after manufacture and post 3 months storage
  • Fig 2 In vitro di ssolution profile of Drospirenone composition of Example 1 , 2 and 3
  • the present invention discloses a pharmaceutical composition
  • a pharmaceutical composition comprising an active drug, along with contraceptive kits comprising active daily dosage units.
  • Each active daily dosage unit may comprise an active contraceptive drug such as a progestogen-only contraceptive (POC).
  • POC progestogen-only contraceptive
  • active drug is used to refer to any compound that possess any potential to provide pharmacological effect or other direct effects in the diagnosis, treatment, mitigation, cure and/or prevention of a disorder. See 21 C.F.R. 210.3(b)(7). Additionally, “active drugs” also encompasses those compounds that may go through chemical changes during the manufacturing processes of the pharmaceutical composition and show up in the final drug product in an altered form may provide a pharmacological activity or effect. An “active contraceptive drug” as described herein, thus indicates an active drug that possess considerable contraceptive ability to prevent pregnancy when administered in an effective amount to a female patient.
  • the active contraceptive drug may possibly prevent pregnancy through several contraceptive properties which includes, but are not limited to ability to inhibit ovulation, to thicken the cervical mucus to reduce sperm viability and penetration and/or to prevent or impede embryo embedding.
  • the POCs may be selected from one or more of the group comprising of drospirenone, 17-hydroxy progesterone esters, 19 -nor- 17 -hydroxy progesterone esters, 17.alpha.-ethinyltestosterone and derivatives thereof, 17.alpha.-ethinyl-19-nor-testosterone and derivatives thereof, norethindrone, norethindrone acetate, norgestrienone, norelgestromin, norgestrel, ethynodiol diacetate, dydrogesterone, medroxy-progesterone acetate, norethynodrel, etonorgestrel, n
  • the active ingredient in the POC may be drospirenone, wherein drospirenone is the only active ingredient present in the pharmaceutical composition of the present invention.
  • Drospirenone possess an anti-mineralocorticoid property which results in amplified potassium excretion and consequently leads to an increased plasma level of potassium. Further, the Cmax of drospirenone has been found to influence to the Cmax of potassium released on administration of drospirenone. Thus, administration of drospirenone may lead to hyperkalemia through the intensified release of potassium. Hyperkalemia has been found be able to induce a number of conditions for instance increased heart rate or palpitations, dizziness, muscle weakness as well as cardiac arrhythmia.
  • each daily dosage unit may include a pharmaceutical composition comprising drospirenone.
  • the said pharmaceutical comprising an active contraceptive drug may comprise drospirenone, without estrogen.
  • the active daily dosage unit comprising pharmaceutical composition that include solely drospirenone as the active contraceptive drug is found to effectively prevent pregnancy when administered to a woman of child-bearing age, daily over a period of 21 to 28 consecutive days.
  • progestogen-only contraceptive or "progestogen-only Contraceptive pill” means a pharmaceutical composition or a tablet or a contraceptive comprising only a progestogens as sole contraceptive agent without any estrogen.
  • This invention encompasses a pharmaceutical composition, which comprises of the active ingredient drospirenone in a non-micronized amorphous form.
  • non-micronized amorphous form of drospirenone is achieved by solubilizing the active contraceptive drug in the organic solvent with addition of hydrophobic polymers and co-polymers, selected from a group comprising of acrylic polymers including without limitation copolymers of methyl acrylate, methyl methacrylate and methacrylic acid, epoxy polymers, polyethylene polymers, polystyrene polymers, polyvinylchloride (PVC) polymer, polytetrafluorethylene polymer, polydimethylsiloxane polymer, polyesters, and polyurethanes, in an organic solvent, and further spray drying the said solution of drug and polymer in organic solvent in fluidized bed processor.
  • PVC polyvinylchloride
  • the organic solvent is selected from a group comprising of aromatic compounds, alcohols, aldehydes, ketones, hydrocarbons, esters and ethers.
  • the organic solvent is selected from, chloroform, toluene, ethanol, methanol, isopropanol, acetone, acetonitrile, formaldehyde, dimethyl formaldehyde, DMSO and carbon tetrachloride.
  • the hydrophobic polymers encompasses acrylic polymers including without limitation copolymers of methyl acrylate, methyl methacrylate and methacrylic acid, epoxy polymers, polyethylene polymers, polystyrene polymers, polyvinylchloride (PVC) polymer, polytetrafluorethylene polymer, poly dimethylsiloxane polymer, polyesters, and polyurethanes.
  • acrylic polymers including without limitation copolymers of methyl acrylate, methyl methacrylate and methacrylic acid, epoxy polymers, polyethylene polymers, polystyrene polymers, polyvinylchloride (PVC) polymer, polytetrafluorethylene polymer, poly dimethylsiloxane polymer, polyesters, and polyurethanes.
  • Plasticizers can be used in combination with the hydrophobic polymers. Suitable plasticizers can be selected from the group comprising of dibutyl sebacate, triacetin, triethyl-citrate, acetyl tributyl citrate, acetyl triethyl citrate polyethylene glycol, polyethylene glycol monomethyl ether, glycerin, sorbitol sorbitan solutions, castor oil, diacetylated monoglycerides.
  • Diluents are selected from a group comprising lactose, celluloses and cellulose derivatives, such as microcrystalline cellulose, powder cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, or combination thereof.
  • the pharmaceutical composition of the present invention may further comprise one or more lubricants selected from the group comprising of stearic acid and derivatives thereof, such as calcium stearate, sodium stearyl fumarate or magnesium stearate, glycerol stearate and hydrogenated vegetable oil or combination thereof.
  • stearic acid and derivatives thereof such as calcium stearate, sodium stearyl fumarate or magnesium stearate, glycerol stearate and hydrogenated vegetable oil or combination thereof.
  • the amorphous drospirenone refers to ideally more than about 99 wt% drospirenone of the total weight of drospirenone is present in amorphous form. In a specific embodiment about 100 wt% of drospirenone of the total weight of drospirenone is present in amorphous form. And no crystalline drospirenone can be detected in the concerned pharmaceutical composition in particular through measurement of powder X-ray diffraction (P-XRD or X-ray diffraction (XRD) pattern.
  • P-XRD powder X-ray diffraction
  • XRD X-ray diffraction
  • non-micronized active ingredient in the present invention refers to amorphous active ingredient obtained without subjecting the active ingredient to any traditional physical size reduction methods like milling, grinding, cutting, crushing, bashing, homogenizing, etc., nor any advanced size reduction techniques like anti- solvent precipitation method, rapid expansion of supercritical fluid or particles from gas saturated solutions, etc.
  • non-micronized drospirenone encompasses particles having particle size distribution such that not less than 30% of the particles are retained on #140 mesh (ASTM).
  • the daily active dosage units comprises of pharmaceutical composition suitable for oral administration.
  • Such composition include but are not limited to, tablets, caplets, capsules, pills, granules, powders and suspension.
  • the orally administered contraceptive composition in the contraceptive kit which are used as daily active dosage unit, is a solid dosage form which includes but are not limited to, tablets, caplets, capsules, pills, and granules.
  • solid pharmaceutically acceptable excipients and adjuvants selected from the group comprising of diluents, binders, disintegrants and lubricants may optionally be added.
  • the solid pharmaceutical composition in the form of tablets, pills or granules may be prepared using well-known methods such as direct compression, dry granulation and wet granulation.
  • the in-vivo pharmacokinetic profile of drospirenone is directly related to the in-vitro dissolution rate of drospirenone.
  • the in vitro dissolution rate of drospirenone should be such that not more than 50% of drospirenone present originally in the pharmaceutical composition of the present invention is dissolved within 30 minutes.
  • the pharmaceutical compositions comprising non-micronized amorphous drospirenone according to present invention offers a slow in-vitro dissolution rate of drospirenone.
  • a slow in vitro dissolution rate of drospirenone denotes that on subjecting pharmaceutical composition of the present invention to an in vitro dissolution test according to the USP apparatus II (Paddle) Method , the discharge of drospirenone is such that not more than 50% of drospirenone originally present in the pharmaceutical composition of the present invention is dissolved within 30 minutes.
  • “not more than 50% of the drospirenone” refers to no more than 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% of the drospirenone originally present in the pharmaceutical composition comprising drospirenone in non-micronized amorphous form. In a specific embodiments, not above about 40% of the drospirenone initially present in the composition is dissolved within 30 min.
  • the in vitro dissolution rate of any active pharmaceutical agent including drospirenone of the present invention can be evaluated using any of the popular methods available in the prior art.
  • the USP apparatus II (Paddle) Method is preferred for evaluation of the in vitro dissolution rate of drospirenone.
  • a tablet comprising of the active contraceptive drug, namely drospirenone is subjected to 900 mL of purified water with 0.6% Tween 20 at 37° C ( ⁇ 0.5° C) at a stirring rate of 75 rpm.
  • the in vitro dissolution of a tablet comprising of the active contraceptive drug, namely drospirenone is carried out using 900 mL of purified water at 37° C ( ⁇ 0.5° C) at a stirring rate of 50 rpm in USP apparatus II (Paddle).
  • an enhanced bioavailability of the active drug in the patient is achieved when a substantial amount of the active drug initially present in the pharmaceutical composition of the present invention, is released within a rational time range.
  • the in vitro dissolution rate of the active drug should be such that at least 50% of the active drug initially present in the pharmaceutical compositions of the present invention, gets dissolved within a time range from about 3 hours to about 4 hours.
  • the said pharmaceutical composition comprising drospirenone is found to possess a significant bioavailability when, about at least 50% of the drospirenone initially present in the pharmaceutical compositions of the present invention gets dissolved in a time range from about 3 hours to about 4 hours.
  • the present invention focuses on a pharmaceutical composition comprising drospirenone for inducing contraception, in which the in vitro dissolution rate of the drospirenone is such that about not more than 50% of the said drospirenone gets dissolved within 30 minutes and about at least 50% of the drospirenone gets dissolved in a time range from 3 hours to 4 hours when subjected to an in vitro dissolution test according to the USP apparatus II (Paddle) Method.
  • “time range from about 3 hours to about 4 hours” denotes to a time range from 3.25 hours, to 3.5 hours, and from 3.75 hours, to 4 hours.
  • “About at least 50% of drospirenone” incorporates at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, at least 88%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, and at least 99.5%.
  • the active drug in conjugation with a hydrophobic polymer is solubilized in an organic solvent, and the solution is further dried on diluent particles using fluidized bed processor, which results in formation of amorphous particles of active drug coated with hydrophobic polymers leading to retardation of dissolution rate.
  • the hydrophobic polymers encompasses acrylic polymers including without limitation copolymers of methyl acrylate, methyl methacrylate and methacrylic acid, epoxy polymers, polyethylene polymers, polystyrene polymers, polyvinylchloride (PVC) polymer, polytetrafluorethylene polymer, polydimethylsiloxane polymer, polyesters, and polyurethanes.
  • acrylic polymers including without limitation copolymers of methyl acrylate, methyl methacrylate and methacrylic acid, epoxy polymers, polyethylene polymers, polystyrene polymers, polyvinylchloride (PVC) polymer, polytetrafluorethylene polymer, polydimethylsiloxane polymer, polyesters, and polyurethanes.
  • Diluents are selected from a group comprising celluloses and cellulose derivatives, such as microcrystalline cellulose, powder cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, or combination thereof.
  • the organic solvent is selected from a group comprising of aromatic compounds, alcohols, aldehydes, ketones, hydrocarbons, esters and ethers.
  • the organic solvent is selected from, chloroform, toluene, ethanol, methanol, isopropanol, acetone, acetonitrile, formaldehyde, dimethyl formaldehyde, DMSO and carbon tetrachloride.
  • the non-micronized amorphous drospirenone containing composition when administered orally relates to a controlled dissolution rate and hence results in a reduced plasma Cmax for drospirenone.
  • a reduced plasma Cmax for drospirenone would consequently diminish the discharge of potassium in plasma.
  • the pharmaceutical composition according to the present is expected to improve the tolerance for drospirenone in women already susceptible to hyperkalemia, suffering from kidney, liver or adrenal diseases, and patients having chronic conditions which are treated with long term, daily dosage of medicines like non-steroidal anti-inflammatory drugs (NSAIDs), potassium-sparing diuretics, potassium supplementation medication, Angiotensin-converting enzyme (ACE) inhibitors, angiotensin-11 receptor antagonists and heparin, that may elevate the risk of hyperkalemia.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • ACE Angiotensin-converting enzyme
  • angiotensin-11 receptor antagonists angiotensin-11 receptor antagonists
  • heparin that may elevate the risk of hyperkalemia.
  • the pharmaceutical compositions containing drospirenone in non-micronized amorphous form, with controlled mean Cmax value for drospirenone can be suitably used to formulate any oral pharmaceutical composition with the purpose of improving the tolerance for drospirenone.
  • the pharmaceutical compositions according to the invention may be used as Hormone Replacement Therapy medicaments (HRT).
  • the pharmaceutical composition of the present invention renders a reduced Cmax accompanied by a delayed t m ax and hence, provides an AUCoh-tiast sufficient to deliver a contraceptive effect.
  • the pharmaceutical composition comprising drospirenone, in the present invention exhibits a stable and effective blood level of Drospirenone when administered daily to a female patient. Hence, additional estrogen is not required to be co-administered to ensure cycle stability and contraception. Therefore, this pharmaceutical compositions are appropriate to efficiently surpass the side effects such as increased risk of cardiovascular events which can be induced by estrogen, and thus can be effectively used as Progestogen- Only Contraceptives.
  • the significantly reduced mean Cmax and stable blood plasma concentration of Drospirenone offered by the pharmaceutical compositions of this invention results in less drug plasma concentration fluctuations between two consecutive administrations.
  • these pharmaceutical compositions promises reduced occurrence of abnormal or unprepared bleeding and spotting and improved bleeding profile as compared to conventional POCs.
  • the methods of treatment and administering drospirenone to induce contraception involve accomplishing of a pharmacokinetic profile that comprises of a mean T m ax ranging from at least about 2.2 hrs to about 6 hrs, and a mean Cmax less than about 30 ng/ml, of the contraceptive drug in the patient body.
  • the pharmacokinetic profile is evaluated in said patient after orally administering a single daily dosage unit of the active contraceptive drug to the patient in fasting condition.
  • the pharmacokinetic profile further comprises an AUCoh-tiast, not less than about 300 ng*h/ml.
  • the method of administering the active contraceptive drug may results in development of a pharmacokinetic profile comprising a mean AUCoh-tiast of not less than 350 ng*ml/h, wherein the mean t m ax may vary from about 2.2 hrs to about 6 hrs and the Cmax may range between about 15 ng/ml to about 30 ng/ml.
  • a mean T m ax ranging from at least about 2.2 hrs to about 6 hrs includes a mean T m ax of at least about 2.5 hrs, a mean T m ax of at least about 3.0 hrs, a mean T m ax of at least about 3.5 hrs, a mean T m ax of at least about 4 hrs, a mean Tmax of at least about 5 hrs.
  • the mean T m ax is not acceptable to be over 6 hours in order to maintenance of the bioavailability of Drospirenone significantly.
  • a T m ax may ranges from about 3.0 hrs to about 4.0 hrs.
  • a mean Cmax less than about 30 ng/ml refers to a Cmax which is less than about 28 ng/ml, a Cmax which is less than about 26 ng/ml, a Cmax which is less than about 24 ng/ml, a Cmax which is less than about 22 ng/ml, a Cmax which is less than about 20 ng/ml, a Cmax which is less than about 19 ng/ml, a Cmax which is less than about 18 ng/ml, a Cmax which is less than about 17 ng/ml, a Cmax which is less than about 16 ng/ml, a Cmax which is less than about 15 ng/ml, a Cmax which is less than about 14 ng/ml.
  • the mean Cmax may range from about 15 ng/ml to about 30 ng/ml. According to another specific embodiments, the mean Cmax may range from about 15 ng/ml to about 26 ng/ml.
  • the pharmaceutical compositions comprising only drospirenone, of the present invention are able to maintain the contraceptive effect even when a placebo period is introduced in the course of the contraceptive regimen. Hence, these pharmaceutical compositions provide a greater contraceptive reliability over other progestogen only contraceptive pills, as it allows patients to be recalcitrant towards treatment increasing the risk of unwanted pregnancy.
  • the plasma concentration of drospirenone after administering a daily active dosage unit of the present invention can be evaluated by popular methods which are already known from prior arts, such as liquid chromatography combined with tandem mass spectrometry, an analytical technique defined by Kirk et al (Rapid Communication in Mass Spectrometry, 2006; 20:1247-1252) is disclosed. This technique involves a process of derivatizing the drospirenone with Girard P hydrazine solution for increasing the response of drospirenone during the successive mass spectrometry analysis and others.
  • the contraceptive composition of each active daily dosage unit comprise of drospirenone in amount of at least about 2 mg.
  • drospirenone in an amount of at least about 2 mg may include drospirenone in an amount of at least about 3 mg, drospirenone in an amount of at least about 3.5 mg, and drospirenone in an amount of at least about 4 mg.
  • the active daily dosage units may comprise of the active contraceptive drug in an amount ranging from about 2 mg to about 6 mg.
  • each active daily dosage unit comprise of drospirenone in amount of about 4 mg.
  • the daily dose of drospirenone selected for administration to a female patient can be adjusted on the basis of several factors related to a patient, such as body weight, age, presence of any underlying disease, general health condition, diet of the female patient, application of any other drug that may lead to drug-drug interactions, and others.
  • the pharmaceutical composition of the active daily dosage units comprising an active contraceptive moiety is found to be effective in inhibiting ovulation and provide contraception, when administered once-a-day to a woman over a period of 21 to 28 days daily dosing regimen.
  • the composition of the present invention allows the patient to administer the active daily unit dosage comprising the contraceptive drug for 24 days and skip up to 4 doses within 28-day daily dosing regimen period, after the inceptive doses of the contraceptive drug has successfully established its contraceptive effect in the patient.
  • the 4 doses can be skipped on non-consecutive days or 2 doses of the 4 skipped doses may be on non-consecutive days and 2 skipped doses can be on consecutive days, or only 1 dose of the 4 skipped doses may be on non-consecutive days and 3 skipped doses can be on consecutive days or the 4 skipped 4 doses can be on consecutive days.
  • the 4 doses can be skipped on consecutive days.
  • patient can skip up to two doses of the active contraceptive drug on non- consecutive days, but the two skipped dose of the active contraceptive drug is advised to be procured within about 24 hrs after the two non-consecutive days of skipped dose.
  • the ability to inhibit ovulation is found to be maintained, though the administration of the active daily units comprising the contraceptive drug was deferred for 24 hours in two discrete non-consecutive days within the 28 day daily dosing regimen.
  • contraceptive effect in a patient may be established by the active contraceptive drug after administration of at least a first, at least a second or at least a third 28-day daily dosing regimen to the patient.
  • the patient may need to be administered with 21 to 28 active dosage units comprising an active contraceptive drug in a pharmaceutical composition.
  • the 28- day daily dosing regimen may further comprise administration of 1 to 7 placebos, in the span of the 28-day daily dosing regimen when the active dosage units are not allotted to the patient.
  • the composition of the present invention is suitable for patient, wherein the patient is a female patient and may undergo several conditions which makes them unsuitable for administration of estrogen as well as high peak plasma concentration of drospirenone.
  • such patients encompasses without limiting to women with a higher risk for developing venous thromboembolism on administration of estrogen, acquired or genetic thrombophilia or hypercoagulability, an age of 35 years and above, and above, smoking habits like cigarettes smoking, more vulnerability towards stroke, sickle-cell anemia, increased threat of myocardial infarction, and lactating women.
  • the female patient is deemed to be overweight and obese and thus possess a BMI of about 25.0 kg/m 2 or more.
  • a patient is considered to be overweight if BMI of the patient is about 25.0 kg/m 2 to about 29.9 kg/m 2 or if the BMI of the patient is about 30 kg/m 2 or more.
  • the female patient may possess several other disorders like liver disease, renal disorders, adrenal related disorders, enhanced vulnerability towards hyperkalemia, chronic conditions treated with medicines like non-steroidal anti-inflammatory drugs, potassium-sparing diuretics, potassium supplementation medication, Angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor antagonists and heparin, that may elevate the risk of hyperkalemia.
  • ACE Angiotensin-converting enzyme
  • the present invention also includes contraceptive kits that comprises of packaging units for the daily active dosage units, suitable for providing contraception to patients in need.
  • contraceptive kits of the present invention comprises of one or more packaging units.
  • the “one or more packaging units” may encompass, but not limiting to, 1 packaging unit, 2 packaging units, 3 packaging units, 4 packaging units, 5 packaging units and 6 packaging units or more.
  • the contraceptive kits comprises of one or more packaging units, wherein each packaging unit of the contraceptive kits comprises from 21 to 28 daily active dosage units containing the active contraceptive drug in a non-micronized amorphous form.
  • each packaging unit of the contraceptive kits comprises of active daily units for a 28-day daily dosing regimen, wherein the patient is allowed to skip up to 4 doses within 28-day daily dosing regimen period, after the inceptive doses of the contraceptive drug has successfully established its contraceptive effect in the patient.
  • the 4 doses can be skipped on non-consecutive days. In another specific embodiment, the 4 doses can be skipped on consecutive days.
  • each packaging unit of the contraceptive kit comprises 24 daily dosage units comprising an effective amount of the active contraceptive composition and may optionally comprises of 4 daily dosage units of a pharmaceutically acceptable placebo.
  • each packaging unit of the contraceptive kit comprising daily dosage units for 28-days daily dosing regimen, may be used for a method of administering the contraceptive composition, wherein the patient is allowed to skip up to two doses of the active contraceptive drug on non-consecutive days, but the skipped dose of the active contraceptive drug is procured within about 24 hrs after the two non-consecutive days of skipped doses.
  • contraceptive effect in a patient may be established by the active contraceptive drug after administration of at least a first, at least a second or at least a third 28-day daily dosing regimen to the patient.
  • the contraceptive kit of the present invention may be designed to facilitate each packaging unit to contain 28 active daily dosage units and no daily dosage unit of a pharmaceutically acceptable placebo.
  • Such a contraceptive kit is suitable for the contraceptive method which includes administering drospirenone continuously, without a free-contraceptive period.
  • each packaging unit may optionally comprise from 1 to 7 daily dosage units of a pharmaceutically acceptable placebo.
  • each packaging units of the contraceptive kits may comprise 21 to 27 active daily dosage units consisting of a contraceptive composition and optionally, 1 to 7 daily dosage units of a pharmaceutically acceptable placebo.
  • a contraceptive kit is suitable for the contraceptive method which includes a first phase wherein active daily dosage units of the invention which do not comprise estrogen are administered to the female patient over a period of 21 to 27 consecutive days followed by a second phase wherein no contraceptive composition is administered to the female patient over a period of 1 to 7 consecutive days.
  • the packaging units of the contraceptive kits may comprise of one of the conventional forms typically used for packaging of oral contraceptives.
  • the packaging unit can be a conventional blister pack comprising the requisite number of dosage units in sealed blister pack having a foil, paperboard, cardboard, or plastic backing and enclosed in a suitable cover.
  • Each blister container may be numbered or marked for enhanced convenience and facilitate compliance.
  • the packaging unit of the contraceptive kits may comprise daily dosage units in a specific arrangement to facilitate the intake of the daily dosage unit in an orderly manner, i.e. first of the at least 21 dosage units that contain the composition comprising drospirenone is arranged at the starting, which is optionally followed by 7 or less dosage units comprising a pharmaceutically acceptable placebo, or 7 or less empty blisters.
  • the contraceptive kit of the present invention may further comprise other appropriate components such as instructions for use, storage or handling or patient counseling information.
  • the active daily dosage units contained in the packaging units of the contraceptive kits comprises of the contraceptive drug in non-micronized amorphous form.
  • the active daily dosage units comprising the active contraceptive drug in non- micronized amorphous form provides an in-vitro dissolution rate of the contraceptive composition such that, about not more than 50% of the said drospirenone gets dissolved within 30 minutes and about at least about not more than 50% of the said drospirenone gets dissolved within 30 minutes and about at least 50% of the drospirenone gets dissolved in a time range from 3 hours to 4 hours when subjected to an in vitro dissolution test according to the USP apparatus II (Paddle) Method, and as a result enables the composition of the present invention to accomplish a pharmacokinetic profile that comprises of a mean T m ax ranging from at least about 2.2 hrs to about 6 hrs, a mean Cmax less than about 30 ng/ml of the contraceptive drug, and an AUCoh
  • the pharmaceutical compositions hereby comprises of active contraceptive components which are specifically Progestogen-Only Contraceptives ("POCs") for inhibiting ovulation.
  • POCs Progestogen-Only Contraceptives
  • the POCs may be selected from one or more of the group comprising of drospirenone, 17-hydroxy progesterone esters, l9-nor-17-hydroxy progesterone esters, 17.alpha.- ethinyltestosterone and derivatives thereof, 17. alpha.
  • Example 1 The invention is further illustrated by the following examples without intending to limit the scope of the invention: Example 1
  • the dissolution data at different time points is as below:
  • the dissolution data reflects that the rate of dissolution of the contraceptive composition of Example 1 is such that, about not more than 50% of the said drospirenone gets dissolved within 30 minutes and about at least 50% of the drospirenone gets dissolved in a time range from 3 hours to 4 hours when subjected to an in vitro dissolution test according to the USP apparatus II (Paddle) Method.
  • the dissolution data reflects that the rate of dissolution of the contraceptive composition of Example 2 is such that, about not more than 50% of the said drospirenone gets dissolved within 30 minutes and about at least 50% of the drospirenone gets dissolved in a time range from 3 hours to 4 hours when subjected to an in vitro dissolution test according to the USP apparatus II (Paddle) Method.
  • the dissolution data at different time points is as below:
  • the dissolution data reflects that the rate of dissolution of the contraceptive composition of Example 3 is such that, about not more than 50% of the said drospirenone gets dissolved within 30 minutes and about at least 50% of the drospirenone gets dissolved in a time range from 3 hours to 4 hours when subjected to an in vitro dissolution test according to the USP apparatus II (Paddle) Method.

Abstract

The invention relates to a pharmaceutical composition of drospirenone. The pharmaceutical composition exhibits a slow in vitro dissolution rate of drospirenone and does not contain any estrogen.

Description

SLOW RELEASE DROSPIRENONE TABLET COMPOSITION
FIELD OF THE INVENTION
The present invention relates to compositions of drospirenone. The drospirenone compositions of the present invention exhibit a slow dissolution profile. Further, the compositions are essentially free of any estogenic components and are therefore progestogen-only contraceptives.
BACKGROUND
With emergence of hormonal contraceptives in 1960, oral contraceptive has become the most commonly used method for hormonal contraception. The two most widely established formulations for women who prefer oral hormonal contraception are Combined Oral Contraceptives (COCs), that constitutes specific doses of both estrogen and progestogen; and, Progestogen-Only Contraceptives ("POCs").
COCs have displayed a superior overall contraceptive efficacy and safety record. The progestin component of COCs contributes to the principle contraceptive mechanisms of action, whereas the estrogen component functions for cycle control as well as the ovulation inhibitory action of progestin. Nevertheless, application of COCs is found to develop undesirable health risks like frequent cardiovascular events, other intolerable adverse effects and is not suggested for non-breastfeeding women in the immediate postpartum period or in breastfeeding women during the initial 6 months of breastfeeding.
Estrogen-free, Progestogen-Only Contraceptives (POCs) are a valuable option in women who prefer to take an oral hormonal contraceptive, and are ineligible for, or choose not to use, COCs. Even though POCs may exhibit considerable disadvantages like low contraceptive reliability, daily intake of POCs at the same time without a pill-free or placebo interval, remarkably altered bleeding patterns for women who take POCs leading to amenorrhea or unscheduled bleeding or spotting, but unlike the combined contraceptive pills, POCs possess the benefit of circumventing the administration of estrogens and hence a decreased risk of venous thromboembolism (VTE) and fewer metabolic changes in women seeking oral contraception and are contraindicated for estrogens (due to migraine or cardiovascular risk factors such as hypertension, hyperlipidemias, obesity, diabetes, smoking habits, etc.).
Drospirenone (6b, 7b : 15b, 16b-Dimethylen-3 -oxo- 17 a-pregn-4-ene-21,17- carbolactone; CAS: 67392-87-4) is a synthetic progestogen which closely resemble the pharmacological activity of natural progesterone. Drospirenone can be prepared by widespread methods defined in the prior art, for instance, in U.S. 4,129,564, WO9806738, EPl 1746101 or W02006061309. The method described in W02006061309 may be particularly suitable for preparing drospirenone. Drospirenone ("DRSP") lacks androgenic, glucocorticoid and antiglucocorticoid activity, but exerts robust anti-mineralocorticoid activity by blocking aldosterone receptors, which increases sodium and water excretion. Drospirenone also possess antiandrogenic activity which helps to resist the effects of naturally occurring androgens by hindering the binding of dihydrotestosterone (DHT) to its receptor and inhibiting androgen synthesis in the ovaries helping to treat acne and hirsutism. Also, oral daily doses of at least 3 mg of drospirenone in combination with an estrogen, has been found to effectively inhibit ovulation over a single treatment cycle of 21 days.
Drospirenone as a contraceptive ingredient is commercially available mostly as combined oral pills under the name of Yasmin R™ (3mg DRSP; 0.03mg EE), Yaz R™ (3 mg DRSP; 0.02mg EE), Angeliq R™ (0.5 mg DRSP; Img EE) and Yasminelle R™ (3 mg DRSP; 0.02mg EE) comprising ethinylestradiol (EE) and drospirenone in micronized form, which elevates it’s in vitro dissolution rate leading to rapid absorption and ensures enhanced oral bioavailability. However, these formulations containing micronized Drospirenone, feature a high plasma concentration peak (high Cmax) for drospirenone which may result in certain harmful side effects and also poor general tolerance when hormonal levels fluctuate too much each and every day. These combine oral contraceptives (COCs) further results in adverse effects of estrogen in patients.
The international application W02006128907, or WO2009138224, relates to pharmaceutical compositions comprised of micronized drospirenone in alone or in combination with an estrogen and other excipients, which exhibit a rapid in vitro dissolution of drospirenone. WO2009138224 teaches that, co-milling of drospirenone with an appropriate carrier is an effective method to produce amorphous drospirenone in a co-milled state with pharmaceutically acceptable carrier, which possess rapid in vitro dissolution and accordingly enhanced oral bioavailability. Also, European patent EP1214076B 1, reveals that the micronized form of drospirenone possess considerably enhanced in-vitro dissolution rate, which appears to be a necessary condition for obtaining a good bioavailability via the oral route. The rapid in vitro dissolution rate of drospirenone also result in an improved in vivo absorption of drospirenone which helps drospirenone to surpass its degradation by gastric or intestine environments. According to EP 1214076 B l, rapid in vitro dissolution of drospirenone means that, when the composition comprising active contraceptive drug, is subjected to an in vitro dissolution method such as USP apparatus II (Paddle) Method II, at least 70% of the drospirenone is dissolved within 30 minutes.
Commercially available Progestogen only Contraceptive pills are also available, under the name of Cerazette R™ (Desogestrel), and Slynd R™ (Drospirenone).
W02012000981 teaches a pharmaceutical composition comprising drospirenone in non-micronized and essentially crystallized form, as the sole active pharmaceutical agent, with slow dissolution rate of drospirenone in vitro and which exhibit a significantly reduced mean Cmax value associated with a delayed mean tmax value for drospirenone.
However, WO2009138224 further teaches drospirenone possess a low chemical stability and thus gets rapidly degraded into pharmacologically inactive entity under acidic condition. Chemical and physiological properties of drospirenone gets altered as it undergoes hydrolysis under alkaline conditions.
Further, micronization of a very potent active pharmaceutical agent such as drospirenone, possess several disadvantages like: contamination due to residues of the milling media produced from erosion of surfaces, leading to chemical destabilization of the newly-formed particles; structural changes or amorphous regions or crystal defects created during milling of drug forms may result in thermodynamically unstable particles, leading to amorphous-crystalline interconversions of the drug during storage, alteration of particle size distribution, specific surface area, chemical and physical reactivity, dissolution or overall performance of the drug product; caking and chemical degradation may occur at high grinding temperatures in case of temperature sensitive materials; hazards from dust may become acute during milling or grinding and can be dangerous for health of workers as a result of inhalation of dust generates during milling of a potent drug.
In order to solve the above-mentioned problems related to micronization of drospirenone and effect of micronized drospirenone, there is a need of formulating a pharmaceutical composition comprising drospirenone substantially in a non- micronized amorphous form alone or in combination with a certain pharmaceutically acceptable carrier to achieve a controlled dissolution.
BRIEF SUMMARY
The present invention discloses a pharmaceutical compositions wherein the pharmaceutical compositions hereby comprises of active contraceptive ingredients which are specifically Progestogen-Only Contraceptives ("POCs") for inhibiting ovulation.
The pharmaceutical composition comprising an active contraceptive moiety, is found to be effective when administered for a 28-day daily dosing regimen. A patient is allowed to skip up to 4 doses within 28-day daily dosing regimen period, after the inceptive doses of the contraceptive drug has successfully established its contraceptive effect in the patient. In a specific embodiment, the 4 doses can be skipped on non-consecutive days. In another specific embodiment, the 4 doses can be skipped on consecutive days.
In another embodiment of the present invention, during the 28-days daily dosing regimen, patient can skip up to two doses of the active contraceptive drug on non- consecutive days, but the skipped dose of the active contraceptive drug is procured within about 24 hours after the two non-consecutive days of skipped doses. In another embodiment, the active contraceptive drug may still be able to retain its property of inhibiting ovulation.
In the present invention, contraceptive effect in a patient may be established by the active contraceptive drug after administration of at least a first, at least a second or at least a third 28-day daily dosing regimen to the patient. In the 28-day daily dosing regimen the patient may need to be administered with 21 to 28 active dosage units comprising an active contraceptive drug in a pharmaceutical composition. The 28- day daily dosing regimen may further comprise administration of 1 to 7 placebos, in the span of the 28-day daily dosing regimen when the active dosage units are not allotted to the patient.
In a specific embodiment, the POCs may be selected from one or more of the group comprising of drospirenone, 17-hydroxy progesterone esters, 19-nor-17-hydroxy progesterone esters, 17.alpha.-ethinyltestosterone and derivatives thereof, 17.alpha.-ethinyl-19-nor-testosterone and derivatives thereof, norethindrone, norethindrone acetate, norgestrienone, norelgestromin, norgestrel, ethynodiol diacetate, dydrogesterone, medroxy-progesterone acetate, norethynodrel, etonorgestrel, norgestimate, allylestrenol, medrogestone, gestodene, lynoestrenol, ethisterone, fuingestanol acetate, dimethiderome, cyproterone acetate, levonorgestrel, d- 17.alpha.-acetoxy- 13.beta. -ethyl- 17. alpha.-a-ethinyl-gon-4-en-3- one oxime, cyproterone acetate, desogestrel, chlormadione and dienogest.
In a specific embodiment, the active ingredient in the POC may be drospirenone, wherein drospirenone is the only active ingredient present in the pharmaceutical composition of the present invention. In an embodiment, each daily dose of drospirenone may comprise a dosage amount of at least about 2 mg. In another embodiment, each single dosage of the pharmaceutical composition of the present invention, comprises essentially of 2 mg to 6 mg of Drospirenone. In a specific embodiment, each daily dose of drospirenone can be between 3mg to 4.5mg. In a preferred embodiment the daily dose of drospirenone is 4mg.
In the present invention, the composition comprises of the active contraceptive drug in non-micronized amorphous form. In an embodiment, amorphous form of the active contraceptive drug can be achieved by solubilizing the active contraceptive drug in the organic solvent with the addition of hydrophobic polymers and copolymers, followed by spray drying in fluidized bed processor. According to the present invention, the amorphous drospirenone refers to ideally about 100 wt% drospirenone of the total weight of drospirenone is present in amorphous form. The amorphous dospirenone in the present invention can be designated as a solid that does not confer a crystalline order and thus, is devoid of distinct peaks in a Powder X-ray diffraction (P-XRD) pattern. In the present invention, preferably no crystalline drospirenone is detected through measurement of powder X-ray diffraction (P-XRD).
The pharmaceutical composition of the present invention may additionally comprise desirable pharmaceutically acceptable excipients and adjuvants, selected from the group comprising of diluents, lubricants, hydrophobic polymers, plasticizers.
Hydrophobic polymers used in the pharmaceutical composition of the present invention is selected from group comprising of pharmaceutically acceptable hydrophobic polymers selected from acrylic polymers including without limitation copolymers of methyl acrylate, methyl methacrylate and methacrylic acid, epoxy polymers, polyethylene polymers, polystyrene polymers, polyvinylchloride (PVC) polymer, polytetrafluorethylene polymer, polydimethylsiloxane polymer, polyesters, and polyurethanes, or combination thereof. In a specific embodiment, the polymer is an acrylic polymer Plasticizers can be used in combination with the hydrophobic polymers. Suitable plasticizers can be selected from the group comprising of dibutyl sebacate, triacetin, triethyl-citrate, acetyl tributyl citrate, acetyl triethyl citrate polyethylene glycol, polyethylene glycol monomethyl ether, glycerin, sorbitol sorbitan solutions, castor oil, diacetylated monoglycerides.
Diluents are selected from a group comprising celluloses and cellulose derivatives, such as microcrystalline cellulose, powder cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, or combination thereof.
The pharmaceutical composition of the present invention may further comprise one or more lubricants selected from stearic acid and derivatives thereof, such as calcium stearate, sodium stearyl fumarate or magnesium stearate, glycerol stearate and hydrogenated vegetable oil or combination thereof.
In an embodiment, the patient is a female patient and may endure several conditions such as, a higher risk for developing venous thromboembolism on administration of estrogen administration of estrogen, acquired or genetic thrombophilia or hypercoagulability, an age of 35 years and above, and above, smoking habits like cigarettes smoking, more vulnerable towards stroke, sickle-cell anemia, increased threat of myocardial infarction, and lactating women. In another embodiment, the female patient is deemed to be overweight and obese and thus possess a BMI of about 25.0 kg/m2 or more. In a specific embodiment, as per weight standards set by WHO a patient is considered to be overweight if BMI of the patient is about 25.0 kg/m2 to about 29.9 kg/m2 or if the BMI of the patient is about 30 kg/m2 or more.
Women with overweight and obesity are more likely to undergo critical adverse reactions due to administration of the contraceptive medicaments. Accordingly, these patients presumably discontinue the contraceptive treatment at an early stage resulting in an increased risk of pregnancy compared to female patients with normal weight under contraceptive treatment.
In the present invention, the female patient may possess several other disorders like liver disease, renal disorders, adrenal related disorders, enhanced vulnerability towards hyperkalemia, chronic conditions treated with medicines like non-steroidal anti-inflammatory drugs, potassium-sparing diuretics, potassium supplementation medication, Angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor antagonists and heparin, that may elevate the risk of hyperkalemia.
In an embodiment, evaluation of the pharmaceutical compositions comprising active contraceptive drugs in a non-micronized amorphous form, by dissolution tests is disclosed, wherein the daily active oral dosage unit comprising at least about 2mg of the contraceptive moiety is subjected to an in vitro dissolution test according to the USP apparatus II (Paddle) Method . In one embodiment of the present invention, the dissolution profile is found to be such that (i) not more than 50% of the active drug initially available in the daily active dosage unit is dissolved within 30 minutes, and (ii) at least 50% of the active drug is found to be dissolved within a time range from about 3 hours to about 4 hours.
In another embodiment, the methods of treatment and administering an active contraceptive drug may include building a pharmacokinetic profile that comprises of mean Tmax ranging from about 2.2 hrs to about 6 hrs, and a mean Cmax less than about 30 ng/ml, of the contraceptive drug in the patient body. The pharmacokinetic profile is evaluated in said patient after orally administering a single daily dosage unit of the active contraceptive drug to the patient in fasting condition. In a specific embodiment, the pharmacokinetic profile further comprises an AUCoh-tiast, not less than about 300 ng*h/ml. In another specific embodiment, the AUCoh-tiast is not less than about 350 ng*h/ml.
The pharmaceutical composition may be formulated as a single daily active dosage unit for administration to a patient having a BMI of about 25 kg/m2 or more for at least a portion of a treatment cycle. In one embodiment, after the administration of the pharmaceutical composition for initial treatment cycle, the pharmaceutical composition reduces the number of days of bleeding events in the patient that exceeds an average of about 20%, about 15%, about 10%, about 8%, or about 5% per treatment cycle in consecutive treatment cycles of administration. The embodiments also relate to kits that comprises of several packaging units. These packaging unit comprises dosage units with an active drug that provides certain pharmacokinetic parameters. In a specific embodiment, the packaging units in the kits, comprises 21 to 28 daily active dosage units comprising an active drug and wherein a single active dosage unit.
BRIEF DESCRIPTION OF THE FIGURES
Fig 1: Overlay PXRDs of Drospirenone active pharmaceutical ingredient used; Drospirenone composition after manufacture and post 3 months storage; Placebo composition after manufacture and post 3 months storage
Fig 2: In vitro di ssolution profile of Drospirenone composition of Example 1 , 2 and 3
DETAILED DESCRIPTION
The present invention discloses a pharmaceutical composition comprising an active drug, along with contraceptive kits comprising active daily dosage units. Each active daily dosage unit may comprise an active contraceptive drug such as a progestogen-only contraceptive (POC).
In the present invention, the term "active drug" is used to refer to any compound that possess any potential to provide pharmacological effect or other direct effects in the diagnosis, treatment, mitigation, cure and/or prevention of a disorder. See 21 C.F.R. 210.3(b)(7). Additionally, "active drugs" also encompasses those compounds that may go through chemical changes during the manufacturing processes of the pharmaceutical composition and show up in the final drug product in an altered form may provide a pharmacological activity or effect. An "active contraceptive drug" as described herein, thus indicates an active drug that possess considerable contraceptive ability to prevent pregnancy when administered in an effective amount to a female patient. The active contraceptive drug may possibly prevent pregnancy through several contraceptive properties which includes, but are not limited to ability to inhibit ovulation, to thicken the cervical mucus to reduce sperm viability and penetration and/or to prevent or impede embryo embedding. In a specific embodiment, the POCs may be selected from one or more of the group comprising of drospirenone, 17-hydroxy progesterone esters, 19 -nor- 17 -hydroxy progesterone esters, 17.alpha.-ethinyltestosterone and derivatives thereof, 17.alpha.-ethinyl-19-nor-testosterone and derivatives thereof, norethindrone, norethindrone acetate, norgestrienone, norelgestromin, norgestrel, ethynodiol diacetate, dydrogesterone, medroxy-progesterone acetate, norethynodrel, etonorgestrel, norgestimate, allylestrenol, medrogestone, gestodene, lynoestrenol, ethisterone, fuingestanol acetate, dimethiderome, cyproterone acetate, levonorgestrel, d- 17. alpha. -acetoxy- 13. beta.-ethyl- 17. alpha. -a-ethinyl-gon-4-en-3- one oxime, cyproterone acetate, desogestrel, chlormadione and dienogest.
In a specific embodiment, the active ingredient in the POC may be drospirenone, wherein drospirenone is the only active ingredient present in the pharmaceutical composition of the present invention.
Drospirenone possess an anti-mineralocorticoid property which results in amplified potassium excretion and consequently leads to an increased plasma level of potassium. Further, the Cmax of drospirenone has been found to influence to the Cmax of potassium released on administration of drospirenone. Thus, administration of drospirenone may lead to hyperkalemia through the intensified release of potassium. Hyperkalemia has been found be able to induce a number of conditions for instance increased heart rate or palpitations, dizziness, muscle weakness as well as cardiac arrhythmia.
In a specific embodiment, each daily dosage unit may include a pharmaceutical composition comprising drospirenone. In preferred embodiments, the said pharmaceutical comprising an active contraceptive drug may comprise drospirenone, without estrogen. The active daily dosage unit comprising pharmaceutical composition that include solely drospirenone as the active contraceptive drug, is found to effectively prevent pregnancy when administered to a woman of child-bearing age, daily over a period of 21 to 28 consecutive days. According to the present invention, "progestogen-only contraceptive", or "progestogen-only Contraceptive pill" means a pharmaceutical composition or a tablet or a contraceptive comprising only a progestogens as sole contraceptive agent without any estrogen.
Pharmaceutical Compositions
This invention encompasses a pharmaceutical composition, which comprises of the active ingredient drospirenone in a non-micronized amorphous form. In an embodiment, non-micronized amorphous form of drospirenone is achieved by solubilizing the active contraceptive drug in the organic solvent with addition of hydrophobic polymers and co-polymers, selected from a group comprising of acrylic polymers including without limitation copolymers of methyl acrylate, methyl methacrylate and methacrylic acid, epoxy polymers, polyethylene polymers, polystyrene polymers, polyvinylchloride (PVC) polymer, polytetrafluorethylene polymer, polydimethylsiloxane polymer, polyesters, and polyurethanes, in an organic solvent, and further spray drying the said solution of drug and polymer in organic solvent in fluidized bed processor.
The organic solvent is selected from a group comprising of aromatic compounds, alcohols, aldehydes, ketones, hydrocarbons, esters and ethers. In a specific embodiments, the organic solvent is selected from, chloroform, toluene, ethanol, methanol, isopropanol, acetone, acetonitrile, formaldehyde, dimethyl formaldehyde, DMSO and carbon tetrachloride.
The hydrophobic polymers, as described herein encompasses acrylic polymers including without limitation copolymers of methyl acrylate, methyl methacrylate and methacrylic acid, epoxy polymers, polyethylene polymers, polystyrene polymers, polyvinylchloride (PVC) polymer, polytetrafluorethylene polymer, poly dimethylsiloxane polymer, polyesters, and polyurethanes.
Plasticizers can be used in combination with the hydrophobic polymers. Suitable plasticizers can be selected from the group comprising of dibutyl sebacate, triacetin, triethyl-citrate, acetyl tributyl citrate, acetyl triethyl citrate polyethylene glycol, polyethylene glycol monomethyl ether, glycerin, sorbitol sorbitan solutions, castor oil, diacetylated monoglycerides.
Diluents, as described herein, are selected from a group comprising lactose, celluloses and cellulose derivatives, such as microcrystalline cellulose, powder cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, or combination thereof.
The pharmaceutical composition of the present invention may further comprise one or more lubricants selected from the group comprising of stearic acid and derivatives thereof, such as calcium stearate, sodium stearyl fumarate or magnesium stearate, glycerol stearate and hydrogenated vegetable oil or combination thereof.
According to the present invention, the amorphous drospirenone refers to ideally more than about 99 wt% drospirenone of the total weight of drospirenone is present in amorphous form. In a specific embodiment about 100 wt% of drospirenone of the total weight of drospirenone is present in amorphous form. And no crystalline drospirenone can be detected in the concerned pharmaceutical composition in particular through measurement of powder X-ray diffraction (P-XRD or X-ray diffraction (XRD) pattern.
Further the non-micronized active ingredient in the present invention, refers to amorphous active ingredient obtained without subjecting the active ingredient to any traditional physical size reduction methods like milling, grinding, cutting, crushing, bashing, homogenizing, etc., nor any advanced size reduction techniques like anti- solvent precipitation method, rapid expansion of supercritical fluid or particles from gas saturated solutions, etc. Further, non-micronized drospirenone encompasses particles having particle size distribution such that not less than 30% of the particles are retained on #140 mesh (ASTM).
According to the present invention, the daily active dosage units comprises of pharmaceutical composition suitable for oral administration. Such composition include but are not limited to, tablets, caplets, capsules, pills, granules, powders and suspension.
According to a specific embodiment of the present invention, the orally administered contraceptive composition in the contraceptive kit, which are used as daily active dosage unit, is a solid dosage form which includes but are not limited to, tablets, caplets, capsules, pills, and granules.
Further, for formulation of said solid forms such as tablets or pills, desirable pharmaceutically acceptable excipients and adjuvants, selected from the group comprising of diluents, binders, disintegrants and lubricants may optionally be added. The solid pharmaceutical composition in the form of tablets, pills or granules may be prepared using well-known methods such as direct compression, dry granulation and wet granulation.
According to the present invention, the in-vivo pharmacokinetic profile of drospirenone, is directly related to the in-vitro dissolution rate of drospirenone. And to maintain a pharmacokinetic profile for drospirenone as described above, the in vitro dissolution rate of drospirenone should be such that not more than 50% of drospirenone present originally in the pharmaceutical composition of the present invention is dissolved within 30 minutes.
In an embodiment, the pharmaceutical compositions comprising non-micronized amorphous drospirenone according to present invention, offers a slow in-vitro dissolution rate of drospirenone. "A slow in vitro dissolution rate of drospirenone” denotes that on subjecting pharmaceutical composition of the present invention to an in vitro dissolution test according to the USP apparatus II (Paddle) Method , the discharge of drospirenone is such that not more than 50% of drospirenone originally present in the pharmaceutical composition of the present invention is dissolved within 30 minutes.
According to an embodiment of the present invention, “not more than 50% of the drospirenone” refers to no more than 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% of the drospirenone originally present in the pharmaceutical composition comprising drospirenone in non-micronized amorphous form. In a specific embodiments, not above about 40% of the drospirenone initially present in the composition is dissolved within 30 min.
The in vitro dissolution rate of any active pharmaceutical agent including drospirenone of the present invention, can be evaluated using any of the popular methods available in the prior art. According to one embodiment, the USP apparatus II (Paddle) Method is preferred for evaluation of the in vitro dissolution rate of drospirenone. In this method, a tablet comprising of the active contraceptive drug, namely drospirenone is subjected to 900 mL of purified water with 0.6% Tween 20 at 37° C (±0.5° C) at a stirring rate of 75 rpm. According to one another embodiment, the in vitro dissolution of a tablet comprising of the active contraceptive drug, namely drospirenone is carried out using 900 mL of purified water at 37° C (±0.5° C) at a stirring rate of 50 rpm in USP apparatus II (Paddle).
Furthermore, according to another embodiment of the present invention, an enhanced bioavailability of the active drug in the patient is achieved when a substantial amount of the active drug initially present in the pharmaceutical composition of the present invention, is released within a rational time range. The in vitro dissolution rate of the active drug should be such that at least 50% of the active drug initially present in the pharmaceutical compositions of the present invention, gets dissolved within a time range from about 3 hours to about 4 hours. In a specific embodiment, the said pharmaceutical composition comprising drospirenone is found to possess a significant bioavailability when, about at least 50% of the drospirenone initially present in the pharmaceutical compositions of the present invention gets dissolved in a time range from about 3 hours to about 4 hours.
Hence, the present invention focuses on a pharmaceutical composition comprising drospirenone for inducing contraception, in which the in vitro dissolution rate of the drospirenone is such that about not more than 50% of the said drospirenone gets dissolved within 30 minutes and about at least 50% of the drospirenone gets dissolved in a time range from 3 hours to 4 hours when subjected to an in vitro dissolution test according to the USP apparatus II (Paddle) Method. In a specific non-limiting embodiment, “time range from about 3 hours to about 4 hours” denotes to a time range from 3.25 hours, to 3.5 hours, and from 3.75 hours, to 4 hours.
In another specific non-limiting embodiment, “About at least 50% of drospirenone” incorporates at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, at least 88%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, and at least 99.5%.
According to the present invention, the active drug in conjugation with a hydrophobic polymer, is solubilized in an organic solvent, and the solution is further dried on diluent particles using fluidized bed processor, which results in formation of amorphous particles of active drug coated with hydrophobic polymers leading to retardation of dissolution rate.
The hydrophobic polymers, as described herein encompasses acrylic polymers including without limitation copolymers of methyl acrylate, methyl methacrylate and methacrylic acid, epoxy polymers, polyethylene polymers, polystyrene polymers, polyvinylchloride (PVC) polymer, polytetrafluorethylene polymer, polydimethylsiloxane polymer, polyesters, and polyurethanes.
Diluents, as described herein, are selected from a group comprising celluloses and cellulose derivatives, such as microcrystalline cellulose, powder cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, or combination thereof.
The organic solvent is selected from a group comprising of aromatic compounds, alcohols, aldehydes, ketones, hydrocarbons, esters and ethers. In a specific embodiments, the organic solvent is selected from, chloroform, toluene, ethanol, methanol, isopropanol, acetone, acetonitrile, formaldehyde, dimethyl formaldehyde, DMSO and carbon tetrachloride.
Also, according to the present invention, the non-micronized amorphous drospirenone containing composition when administered orally, relates to a controlled dissolution rate and hence results in a reduced plasma Cmax for drospirenone. A reduced plasma Cmax for drospirenone would consequently diminish the discharge of potassium in plasma. Therefore, the pharmaceutical composition according to the present, is expected to improve the tolerance for drospirenone in women already susceptible to hyperkalemia, suffering from kidney, liver or adrenal diseases, and patients having chronic conditions which are treated with long term, daily dosage of medicines like non-steroidal anti-inflammatory drugs (NSAIDs), potassium-sparing diuretics, potassium supplementation medication, Angiotensin-converting enzyme (ACE) inhibitors, angiotensin-11 receptor antagonists and heparin, that may elevate the risk of hyperkalemia.
According to the present invention, the pharmaceutical compositions containing drospirenone in non-micronized amorphous form, with controlled mean Cmax value for drospirenone, can be suitably used to formulate any oral pharmaceutical composition with the purpose of improving the tolerance for drospirenone. The pharmaceutical compositions according to the invention may be used as Hormone Replacement Therapy medicaments (HRT).
The pharmaceutical composition of the present invention renders a reduced Cmax accompanied by a delayed tmax and hence, provides an AUCoh-tiast sufficient to deliver a contraceptive effect. The pharmaceutical composition comprising drospirenone, in the present invention, exhibits a stable and effective blood level of Drospirenone when administered daily to a female patient. Hence, additional estrogen is not required to be co-administered to ensure cycle stability and contraception. Therefore, this pharmaceutical compositions are appropriate to efficiently surpass the side effects such as increased risk of cardiovascular events which can be induced by estrogen, and thus can be effectively used as Progestogen- Only Contraceptives. Also, the significantly reduced mean Cmax and stable blood plasma concentration of Drospirenone offered by the pharmaceutical compositions of this invention, results in less drug plasma concentration fluctuations between two consecutive administrations. Thus, these pharmaceutical compositions promises reduced occurrence of abnormal or unprepared bleeding and spotting and improved bleeding profile as compared to conventional POCs. In another embodiment, the methods of treatment and administering drospirenone to induce contraception, involve accomplishing of a pharmacokinetic profile that comprises of a mean Tmax ranging from at least about 2.2 hrs to about 6 hrs, and a mean Cmax less than about 30 ng/ml, of the contraceptive drug in the patient body. The pharmacokinetic profile is evaluated in said patient after orally administering a single daily dosage unit of the active contraceptive drug to the patient in fasting condition. In an embodiment, the pharmacokinetic profile further comprises an AUCoh-tiast, not less than about 300 ng*h/ml. According to a specific embodiment, the method of administering the active contraceptive drug may results in development of a pharmacokinetic profile comprising a mean AUCoh-tiast of not less than 350 ng*ml/h, wherein the mean tmax may vary from about 2.2 hrs to about 6 hrs and the Cmax may range between about 15 ng/ml to about 30 ng/ml.
As described herein, “a mean Tmax ranging from at least about 2.2 hrs to about 6 hrs” includes a mean Tmax of at least about 2.5 hrs, a mean Tmax of at least about 3.0 hrs, a mean Tmax of at least about 3.5 hrs, a mean Tmax of at least about 4 hrs, a mean Tmax of at least about 5 hrs. However, the mean Tmax is not acceptable to be over 6 hours in order to maintenance of the bioavailability of Drospirenone significantly. In some specific embodiments, a Tmax may ranges from about 3.0 hrs to about 4.0 hrs.
Also, as described herein, “a mean Cmax less than about 30 ng/ml” refers to a Cmax which is less than about 28 ng/ml, a Cmax which is less than about 26 ng/ml, a Cmax which is less than about 24 ng/ml, a Cmax which is less than about 22 ng/ml, a Cmax which is less than about 20 ng/ml, a Cmax which is less than about 19 ng/ml, a Cmax which is less than about 18 ng/ml, a Cmax which is less than about 17 ng/ml, a Cmax which is less than about 16 ng/ml, a Cmax which is less than about 15 ng/ml, a Cmax which is less than about 14 ng/ml. According to a specific embodiments, the mean Cmax may range from about 15 ng/ml to about 30 ng/ml. According to another specific embodiments, the mean Cmax may range from about 15 ng/ml to about 26 ng/ml. The pharmaceutical compositions comprising only drospirenone, of the present invention are able to maintain the contraceptive effect even when a placebo period is introduced in the course of the contraceptive regimen. Hence, these pharmaceutical compositions provide a greater contraceptive reliability over other progestogen only contraceptive pills, as it allows patients to be recalcitrant towards treatment increasing the risk of unwanted pregnancy.
The plasma concentration of drospirenone after administering a daily active dosage unit of the present invention, can be evaluated by popular methods which are already known from prior arts, such as liquid chromatography combined with tandem mass spectrometry, an analytical technique defined by Kirk et al (Rapid Communication in Mass Spectrometry, 2006; 20:1247-1252) is disclosed. This technique involves a process of derivatizing the drospirenone with Girard P hydrazine solution for increasing the response of drospirenone during the successive mass spectrometry analysis and others.
In the present invention, the contraceptive composition of each active daily dosage unit comprise of drospirenone in amount of at least about 2 mg. As described herein, “drospirenone in an amount of at least about 2 mg” may include drospirenone in an amount of at least about 3 mg, drospirenone in an amount of at least about 3.5 mg, and drospirenone in an amount of at least about 4 mg. According to another embodiment, the active daily dosage units may comprise of the active contraceptive drug in an amount ranging from about 2 mg to about 6 mg. In a specific embodiment, the “amount ranging from about 2 mg to about 6 mg”, as described herein, may incorporate amount of 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, and 6 mg. In a specific embodiment, each active daily dosage unit comprise of drospirenone in amount of about 4 mg.
However, the daily dose of drospirenone selected for administration to a female patient can be adjusted on the basis of several factors related to a patient, such as body weight, age, presence of any underlying disease, general health condition, diet of the female patient, application of any other drug that may lead to drug-drug interactions, and others. The pharmaceutical composition of the active daily dosage units comprising an active contraceptive moiety, is found to be effective in inhibiting ovulation and provide contraception, when administered once-a-day to a woman over a period of 21 to 28 days daily dosing regimen. Further, in an embodiment, the composition of the present invention allows the patient to administer the active daily unit dosage comprising the contraceptive drug for 24 days and skip up to 4 doses within 28-day daily dosing regimen period, after the inceptive doses of the contraceptive drug has successfully established its contraceptive effect in the patient. In a specific embodiment, the 4 doses can be skipped on non-consecutive days or 2 doses of the 4 skipped doses may be on non-consecutive days and 2 skipped doses can be on consecutive days, or only 1 dose of the 4 skipped doses may be on non-consecutive days and 3 skipped doses can be on consecutive days or the 4 skipped 4 doses can be on consecutive days. In another specific embodiment, the 4 doses can be skipped on consecutive days.
In another embodiment of the present invention, during the 28-days daily dosing regimen, patient can skip up to two doses of the active contraceptive drug on non- consecutive days, but the two skipped dose of the active contraceptive drug is advised to be procured within about 24 hrs after the two non-consecutive days of skipped dose. In another embodiment, the ability to inhibit ovulation is found to be maintained, though the administration of the active daily units comprising the contraceptive drug was deferred for 24 hours in two discrete non-consecutive days within the 28 day daily dosing regimen.
In the present invention, contraceptive effect in a patient may be established by the active contraceptive drug after administration of at least a first, at least a second or at least a third 28-day daily dosing regimen to the patient. In the 28-day daily dosing regimen the patient may need to be administered with 21 to 28 active dosage units comprising an active contraceptive drug in a pharmaceutical composition. The 28- day daily dosing regimen may further comprise administration of 1 to 7 placebos, in the span of the 28-day daily dosing regimen when the active dosage units are not allotted to the patient. In an embodiment, the composition of the present invention is suitable for patient, wherein the patient is a female patient and may undergo several conditions which makes them unsuitable for administration of estrogen as well as high peak plasma concentration of drospirenone. According to a specific embodiment, such patients encompasses without limiting to women with a higher risk for developing venous thromboembolism on administration of estrogen, acquired or genetic thrombophilia or hypercoagulability, an age of 35 years and above, and above, smoking habits like cigarettes smoking, more vulnerability towards stroke, sickle-cell anemia, increased threat of myocardial infarction, and lactating women. In another embodiment, the female patient is deemed to be overweight and obese and thus possess a BMI of about 25.0 kg/m2 or more. In a specific embodiment, as per weight standards set by WHO a patient is considered to be overweight if BMI of the patient is about 25.0 kg/m2 to about 29.9 kg/m2 or if the BMI of the patient is about 30 kg/m2 or more.
Women with overweight and obesity are more likely to undergo critical adverse reactions due to administration of the contraceptive medicaments. Accordingly, these patients presumably discontinue the contraceptive treatment at an early stage resulting in an increased risk of pregnancy compared to female patients with normal weight under contraceptive treatment.
In the present invention, the female patient may possess several other disorders like liver disease, renal disorders, adrenal related disorders, enhanced vulnerability towards hyperkalemia, chronic conditions treated with medicines like non-steroidal anti-inflammatory drugs, potassium-sparing diuretics, potassium supplementation medication, Angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor antagonists and heparin, that may elevate the risk of hyperkalemia.
The present invention also includes contraceptive kits that comprises of packaging units for the daily active dosage units, suitable for providing contraception to patients in need. In an embodiment, contraceptive kits of the present invention comprises of one or more packaging units. In a specific embodiment, the “one or more packaging units” may encompass, but not limiting to, 1 packaging unit, 2 packaging units, 3 packaging units, 4 packaging units, 5 packaging units and 6 packaging units or more.
In an embodiment of the present invention, the contraceptive kits comprises of one or more packaging units, wherein each packaging unit of the contraceptive kits comprises from 21 to 28 daily active dosage units containing the active contraceptive drug in a non-micronized amorphous form.
In an embodiment of the present invention, each packaging unit of the contraceptive kits comprises of active daily units for a 28-day daily dosing regimen, wherein the patient is allowed to skip up to 4 doses within 28-day daily dosing regimen period, after the inceptive doses of the contraceptive drug has successfully established its contraceptive effect in the patient. In a specific embodiment, the 4 doses can be skipped on non-consecutive days. In another specific embodiment, the 4 doses can be skipped on consecutive days.
In an embodiment, each packaging unit of the contraceptive kit comprises 24 daily dosage units comprising an effective amount of the active contraceptive composition and may optionally comprises of 4 daily dosage units of a pharmaceutically acceptable placebo. In a specific embodiment of the present invention, each packaging unit of the contraceptive kit comprising daily dosage units for 28-days daily dosing regimen, may be used for a method of administering the contraceptive composition, wherein the patient is allowed to skip up to two doses of the active contraceptive drug on non-consecutive days, but the skipped dose of the active contraceptive drug is procured within about 24 hrs after the two non-consecutive days of skipped doses.
In the present invention, contraceptive effect in a patient may be established by the active contraceptive drug after administration of at least a first, at least a second or at least a third 28-day daily dosing regimen to the patient. The contraceptive kit of the present invention, may be designed to facilitate each packaging unit to contain 28 active daily dosage units and no daily dosage unit of a pharmaceutically acceptable placebo. Such a contraceptive kit is suitable for the contraceptive method which includes administering drospirenone continuously, without a free-contraceptive period.
Further, each packaging unit may optionally comprise from 1 to 7 daily dosage units of a pharmaceutically acceptable placebo.
In another embodiment, each packaging units of the contraceptive kits may comprise 21 to 27 active daily dosage units consisting of a contraceptive composition and optionally, 1 to 7 daily dosage units of a pharmaceutically acceptable placebo. Such a contraceptive kit is suitable for the contraceptive method which includes a first phase wherein active daily dosage units of the invention which do not comprise estrogen are administered to the female patient over a period of 21 to 27 consecutive days followed by a second phase wherein no contraceptive composition is administered to the female patient over a period of 1 to 7 consecutive days.
In an embodiment of the present invention, the packaging units of the contraceptive kits, may comprise of one of the conventional forms typically used for packaging of oral contraceptives. In a specific embodiment, the packaging unit can be a conventional blister pack comprising the requisite number of dosage units in sealed blister pack having a foil, paperboard, cardboard, or plastic backing and enclosed in a suitable cover. Each blister container may be numbered or marked for enhanced convenience and facilitate compliance.
The packaging unit of the contraceptive kits, may comprise daily dosage units in a specific arrangement to facilitate the intake of the daily dosage unit in an orderly manner, i.e. first of the at least 21 dosage units that contain the composition comprising drospirenone is arranged at the starting, which is optionally followed by 7 or less dosage units comprising a pharmaceutically acceptable placebo, or 7 or less empty blisters. In an embodiment, the contraceptive kit of the present invention may further comprise other appropriate components such as instructions for use, storage or handling or patient counselling information.
The active daily dosage units contained in the packaging units of the contraceptive kits comprises of the contraceptive drug in non-micronized amorphous form. The active daily dosage units comprising the active contraceptive drug in non- micronized amorphous form, provides an in-vitro dissolution rate of the contraceptive composition such that, about not more than 50% of the said drospirenone gets dissolved within 30 minutes and about at least about not more than 50% of the said drospirenone gets dissolved within 30 minutes and about at least 50% of the drospirenone gets dissolved in a time range from 3 hours to 4 hours when subjected to an in vitro dissolution test according to the USP apparatus II (Paddle) Method, and as a result enables the composition of the present invention to accomplish a pharmacokinetic profile that comprises of a mean Tmax ranging from at least about 2.2 hrs to about 6 hrs, a mean Cmax less than about 30 ng/ml of the contraceptive drug, and an AUCoh-tiast, not less than about 300 ng*h/ml in the patient body after orally administering a single daily dosage unit of the active contraceptive drug to the patient in fasting condition.
According to an embodiment, the pharmaceutical compositions hereby comprises of active contraceptive components which are specifically Progestogen-Only Contraceptives ("POCs") for inhibiting ovulation. In a specific embodiment, the POCs may be selected from one or more of the group comprising of drospirenone, 17-hydroxy progesterone esters, l9-nor-17-hydroxy progesterone esters, 17.alpha.- ethinyltestosterone and derivatives thereof, 17. alpha. -ethinyl- 19-nor-testosterone and derivatives thereof, norethindrone, norethindrone acetate, norgestrienone, norelgestromin, norgestrel, ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel, etonorgestrel, norgestimate, allylestrenol, medrogestone, gestodene, lynoestrenol, ethisterone, fuingestanol acetate, dimethiderome, cyproterone acetate, levonorgestrel, d-17.alpha.-acetoxy-13.beta.- ethyl- 17.alpha.-a-elhinyl-gon-4-en-3-one oxime, cyproterone acetate, desogestrel, chlormadione and dienogest.
The invention is further illustrated by the following examples without intending to limit the scope of the invention: Example 1
Figure imgf000025_0001
Preparation of drospirenone tablets:
1) Dissolve non-micronized Drospirenone, Methacrylic Acid and Methyl Methacrylate Copolymer, Triethyl citrate in Acetone. Stir till to get clear solution.
2) Sift Microcrystalline Cellulose and load in Fluid bed Granulator (FBG).
3) Spray Step-1 solution on premix loaded in FBG bowl (Top Spray Granulation).
4) Dry the granules and sift the resultant granules through suitable sieve.
5) Mix the above granules with sifted Magnesium Stearate to form final blend
6) Compress the blend of Step- 5 into tablets by using the punches.
In-Vitro dissolution of Drospirenone tablets for Example 1
The tablets prepared from method described in Example 1 were subjected to in vitro dissolution. Method used:
Figure imgf000026_0001
The dissolution data at different time points is as below:
Figure imgf000026_0002
The dissolution data reflects that the rate of dissolution of the contraceptive composition of Example 1 is such that, about not more than 50% of the said drospirenone gets dissolved within 30 minutes and about at least 50% of the drospirenone gets dissolved in a time range from 3 hours to 4 hours when subjected to an in vitro dissolution test according to the USP apparatus II (Paddle) Method.
Example 2:
Figure imgf000026_0003
Figure imgf000027_0001
Preparation of drospirenone tablets:
1) Dissolve non-micronized Drospirenone, Copovidone, Methacrylate copolymer in methylene chloride and Ethyl alcohol. Stir till to get clear solution.
2) Sift Microcrystalline Cellulose, Lactose anhydrous and load in Fluid bed Granulator (FBG).
3) Spray Step-1 solution on premix loaded in FBG bowl.
4) Dry the granules till to get desired LOD and sift the resultant granules through suitable sieve.
5) Mix the above granules with sifted Magnesium Stearate to form final blend
6) Compress the blend of Step- 5 into tablets by using punches.
In-Vitro dissolution of Drospirenone tablets of Example 2 The tablets prepared from method described in Example 2 were subjected to in vitro dissolution.
Method used:
Figure imgf000027_0002
The dissolution data at different time points is as below:
Figure imgf000028_0001
The dissolution data reflects that the rate of dissolution of the contraceptive composition of Example 2 is such that, about not more than 50% of the said drospirenone gets dissolved within 30 minutes and about at least 50% of the drospirenone gets dissolved in a time range from 3 hours to 4 hours when subjected to an in vitro dissolution test according to the USP apparatus II (Paddle) Method.
Example 3:
Figure imgf000028_0002
Preparation of drospirenone tablets:
1) Dissolve non-micronized Drospirenone, Triethylcitrate, Methacrylate Copolymer in acetone. Stir to get clear solution.
2) Sift Microcrystalline Cellulose, Croscarmellose Sodium and load in Fluid bed Granulator (FBG).
3) Spray Step-1 solution on premix loaded in FBG bowl.
4) Dry the granules till to get desired LOD and sift the resultant granules through suitable sieve.
5) Mix the above granules with sifted Magnesium Stearate to form final blend
6) Compress the blend of Step- 5 into tablets by using punches.
In-Vitro dissolution of Drospirenone tablets of Example 3
The tablets prepared from method described in Example 2 were subjected to in vitro dissolution. Method used:
Figure imgf000029_0001
The dissolution data at different time points is as below:
Figure imgf000029_0002
Figure imgf000030_0001
The dissolution data reflects that the rate of dissolution of the contraceptive composition of Example 3 is such that, about not more than 50% of the said drospirenone gets dissolved within 30 minutes and about at least 50% of the drospirenone gets dissolved in a time range from 3 hours to 4 hours when subjected to an in vitro dissolution test according to the USP apparatus II (Paddle) Method.

Claims

CLAIMS:
1. A pharmaceutical composition comprising 2 mg to 6 mg of non-micronized amorphous drospirenone and pharmaceutically acceptable excipients such that the pharmaceutical composition when subjected to an in vitro dissolution test according to the USP apparatus II (Paddle) Method, no more than 50% of the drospirenone initially present in the pharmaceutical composition is dissolved within 30 minutes, and wherein the pharmaceutical composition does not contain an estrogen.
2. The pharmaceutical composition of claim 1 wherein the pharmaceutically acceptable excipients comprise diluents, hydrophobic polymers, plasticizers, lubricants.
3. The pharmaceutical composition of claim 2, wherein the diluents are selected from a group comprising of lactose, celluloses and cellulose derivatives, such as microcrystalline cellulose, powder cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, or combination thereof.
4. The pharmaceutical composition of claim 2, wherein the hydrophobic polymers are selected from a group comprising of acrylic polymers, epoxy polymers, polyethylene polymers, polystyrene polymers, polyvinylchloride (PVC) polymer, polytetrafluorethylene polymer, poly dimethylsiloxane polymer, polyesters, polyurethanes or combinations thereof.
5. The pharmaceutical composition of claim 4 wherein the acrylic polymers are Methacrylic acid and methacrylate co-polymer.
6. The pharmaceutical composition of claim 2, wherein the plasticizers are selected from a group comprising of dibutyl sebacate, triacetin, triethyl-citrate, acetyl tributyl citrate, acetyl triethyl citrate polyethylene glycol, polyethylene glycol monomethyl ether, glycerin, sorbitol sorbitan solutions, castor oil, diacetylated monoglycerides or combinations thereof.
7. The pharmaceutical composition of claim 2, wherein the lubricants are selected from a group comprising of stearic acid and derivatives thereof, such as calcium stearate, sodium stearyl fumarate or magnesium stearate, glycerol stearate and hydrogenated vegetable oil or combination thereof.
8. The pharmaceutical composition of claim 1, wherein the composition is prepared by (a) dissolving drospirenone and hydrophobic polymer(s) to form a solution, (b) the solution is sprayed over the diluent(s) and dried to obtain drospirenone loaded granules, (c) the granules of step (b) are blended with lubricant(s), and (d) the lubricated blend is compressed to form a tablet.
PCT/IB2023/051128 2022-02-10 2023-02-08 Slow release drospirenone tablet composition WO2023152658A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202221007175 2022-02-10
IN202221007175 2022-02-10

Publications (1)

Publication Number Publication Date
WO2023152658A1 true WO2023152658A1 (en) 2023-08-17

Family

ID=85382647

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2023/051128 WO2023152658A1 (en) 2022-02-10 2023-02-08 Slow release drospirenone tablet composition

Country Status (1)

Country Link
WO (1) WO2023152658A1 (en)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4129564A (en) 1976-11-16 1978-12-12 Schering, A.G. Patentabteilung Spirolactones
WO1998006738A1 (en) 1996-08-12 1998-02-19 Schering Aktiengesellschaft Process for producing drospirenone and intermediates thereof
EP1214076B1 (en) 1999-08-31 2003-11-19 Schering Aktiengesellschaft Pharmaceutical combination of ethinylestradiol and drospirenone for use as a contraceptive
WO2006061309A1 (en) 2004-12-06 2006-06-15 Industriale Chimica S.R.L. Process for the preparation of drospirenone
WO2006128907A2 (en) 2005-06-03 2006-12-07 Laboratorios León Farma, S.A. Rapidly-dissolving pharmaceutical composition for inhibiting ovulation
WO2009138224A1 (en) 2008-05-14 2009-11-19 Helm Ag Pharmaceutical composition comprising drospirenone
WO2012000981A1 (en) 2010-06-29 2012-01-05 Laboratorios Leon Farma Sa Pharmaceutical composition comprising drospirenone and contraceptive kit
US20120128733A1 (en) * 2010-07-28 2012-05-24 Philippe Perrin Pharmaceutical compositions comprising active drugs, contraceptive kits comprising active drugs, and methods of administering the same

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4129564A (en) 1976-11-16 1978-12-12 Schering, A.G. Patentabteilung Spirolactones
WO1998006738A1 (en) 1996-08-12 1998-02-19 Schering Aktiengesellschaft Process for producing drospirenone and intermediates thereof
EP1214076B1 (en) 1999-08-31 2003-11-19 Schering Aktiengesellschaft Pharmaceutical combination of ethinylestradiol and drospirenone for use as a contraceptive
WO2006061309A1 (en) 2004-12-06 2006-06-15 Industriale Chimica S.R.L. Process for the preparation of drospirenone
WO2006128907A2 (en) 2005-06-03 2006-12-07 Laboratorios León Farma, S.A. Rapidly-dissolving pharmaceutical composition for inhibiting ovulation
WO2009138224A1 (en) 2008-05-14 2009-11-19 Helm Ag Pharmaceutical composition comprising drospirenone
WO2012000981A1 (en) 2010-06-29 2012-01-05 Laboratorios Leon Farma Sa Pharmaceutical composition comprising drospirenone and contraceptive kit
US20120128733A1 (en) * 2010-07-28 2012-05-24 Philippe Perrin Pharmaceutical compositions comprising active drugs, contraceptive kits comprising active drugs, and methods of administering the same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KIRK ET AL., RAPID COMMUNICATION IN MASS SPECTROMETRY, vol. 20, 2006, pages 1247 - 1252

Similar Documents

Publication Publication Date Title
US11291632B2 (en) Synthetic progestogens and pharmaceutical compositions comprising the same
US11478487B1 (en) Synthetic progestogens and pharmaceutical compositions comprising the same
AU2004275470B2 (en) Improved stability of progestogen formulations
US11413249B2 (en) Synthetic progestogens and pharmaceutical compositions comprising the same
WO2023152658A1 (en) Slow release drospirenone tablet composition
AU2011273605B8 (en) Pharmaceutical composition comprising drospirenone and contraceptive kit

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23707476

Country of ref document: EP

Kind code of ref document: A1